Single cell transcriptomics reveals sequential fate selection points and mechanism of cell fate commitment of the neural crest
Ruslan Soldatov2, Marketa Kaucka1, Tatiana Chontorotzea3, Julian Petersen1, Maria Eleni Kastriti3, Natalia Akkuratova3, Ueli Suter4, Viacheslav Dyachuk5, Kaj Fried5, Peter Kharchenko2, Igor Adameyko1,3
1Center for Brain Research, Medical University Vienna, 1090 Vienna, Austria; 2Department of Biomedical Informatics, Harvard Medical School, MA 02115 Boston, USA; 3Department of Physiology and Pharmacology, Karolinska Institutet, 17177 Stockholm, Sweden; 4Institute for Molecular Health Sciences, ETH Zurich, 8093 Zurich, Switzerland; 5Department of Neuroscience, Karolinska Institutet, 17177 Stockholm, Sweden
Neural crest cells are transient embryonic progenitors that are often called 4th germ layer since they give rise to a large number of differentiated cell types in the body. In that regard, neural crest is a great system to study developmental architecture and molecular mechanisms of multiple fate selection. We took advantage of a single cell transcriptomics approach to address fate selection mechanisms in the neural crest. To investigate the positions of cell fate decisions we developed computational methods to reconstruct multiple-branching differentiation trajectories through principal graph modeling. The results showed that cell fate switches operate as sequential bifurcations of choices and enabled comprehensive reconstruction of gene modules associated with major neural crest differentiation patterns and waves of gene regulatory changes. Analysis of the first post-migratory bifurcation point reveals early-biasing and commitment stages of cell fate selection. Fate-specific gene modules are heterogeneously expressed in premigratory neural crest populations, followed by gradual activation and synchronization of fate-specific gene modules leading to compositional differences in pre-bifurcating cell populations. Commitment stage is characterized by mutually exclusive activation of post-bifurcation gene modules.
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